Amyotrophic lateral sclerosis (ALS) results from progressive degeneration of motor neurons. ALS inexorably progresses to paralysis and to death within an average of 5 years. Of the few treatments, none substantially prolongs life or improves the quality of life. A major hurdle to developing effective therapy for ALS is a limited understanding of the disease mechanisms. A recent advance in ALS research comes with the discovery of TDP- 43 proteinopathy and TDP mutation. When overexpressed in transgenic rodents, mutant TDP-43 causes progressive neurodegeneration accompanied by severe glial reaction. To dissect the mechanisms underlying neurodegeneration caused by TDP mutation, we have developed transgenic rats reversibly expressing mutant TDP-43 in neurons or in astrocytes. By microarray analysis, we also have identified candidate genes responsive to glial reaction in mutant TDP-43 transgenic rats. Using TDP-43 transgenic rats (in vivo model) and primary cell cultures (in vitro model) as complementary models, we will resolve the following critical questions regarding TDP-43 pathogenesis: 1) how glial reaction correlates with the neurodegeneration caused by TDP mutation; 2) whether presence of mutant TDP-43 in astrocytes accelerates glial activation; 3) what molecules mediate the propagation of glial reaction in response to TDP mutation; 4) how astrocytes expressing mutant TDP-43 produce neurotoxicity; 5) how expression of mutant TDP-43 in astrocytes affects onset and progression of ALS in transgenic rats; and 6) whether continuous presence of mutant TDP-43 is required for disease progression. Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43. PUBLIC HEALTH RELEVANCE: Using transgenic rats and primary cells as complementary models, this proposal will dissect the mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis and will provide a foundation for developing ALS therapies.